Apparatus for removing chemotherapy compounds from blood

ABSTRACT

A filter apparatus for removing small molecule chemotherapy agents from blood is provided. The filter apparatus comprises a housing with an extraction media comprised of polymer coated carbon cores. Also provided are methods of treating a subject with cancer of an organ or region comprising administering a chemotherapeutic agent to the organ or region, collecting blood laded with chemotherapeutic agent from the isolated organ, filtering the blood laden with chemotherapeutic agent to reduce the chemotherapeutic agent in the blood and returning the blood to the subject.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is a continuation application of U.S. patentapplication Ser. No. 15/651,141 filed Jul. 17, 2017, which is acontinuation of U.S. patent application Ser. No. 13/671,549, filed Nov.7, 2012, now U.S. Pat. No. 9,707,331, which claims the priority benefitof U.S. Provisional Patent Application Ser. No. 61/556,819 filed Nov. 7,2011, and entitled “APPARATUS FOR REMOVING CHEMOTHERAPY COMPOUNDS FROMBLOOD.” The disclosures of the aforementioned Provisional PatentApplication Ser. No. 61/556,819, U.S. patent application Ser. No.15/651,141, and U.S. patent application Ser. No. 13/671,549 are herebyincorporated by reference in their entirety.

BACKGROUND

The systemic presence of toxic chemotherapeutic agents in patientsundergoing chemotherapy has been the cause of great suffering anddiscontinuation of potentially life extending or saving treatment. Wherethe cancer is located to specific organs, various approaches have beentaken to limit this systemic exposure to toxic chemotherapeutic agents.

The liver is an important example because primary and metastatic livertumors are one of the largest causes of cancer deaths in the world.Hepatocellular carcinoma, for example, is one of the most common andlethal malignancies. Curley et al., Annals of Surgical Oncology 1(5):389-399 (1994). In addition, metastases to the liver is the most commondisease progression of a variety of cancers of different origins such ascolorectal adenocarcinoma, ocular melanoma, neuroendocrine tumors, andgastrointestinal sarcoma resulting in oftentimes multifocal andunresectable cancers of the liver. Pingpank et al., J. Clin. Oncol. Vol23 (15): 3465-3474 (2005).

High doses of chemotherapy have been shown to be effective in thetreatment of liver cancers. However, due to the toxicity ofchemotherapeutic agents, the use of high dose therapy has been limited.To overcome problems associated with systemic exposure to chemotherapy,approaches have been taken to limit systemic exposure. A demandingsurgical approach, isolated hepatic perfusion (IHP), has been used toprovide high doses of chemotherapy regionally to the liver. Thedrawbacks to this approach include lack of repeatability for aparticular patient and high mortality due to the surgery. Pingpank etal., J. Clin. Oncol. Vol 23 (15): 3465-3474 (2005).

An alternative approach of great promise has become known aschemosaturation, a technique using catheter technology to percutaneouslydeliver a high dose of chemotherapy to the effected organ and thenremoval of the blood laden with chemotherapeutic agents from the organ,filtration of the blood by extracorporeal filtration, and then return ofthe blood, after the chemotherapeutic agent has been removed, to thepatient.

In hepatic chemosaturation therapy, for example, a percutaneous hepaticperfusion (PHP) procedure intra-arterially delivers high doses ofchemotherapy (anti-cancer agents) directly into the isolated liver,saturating both the liver cells and the tumor cells. The blood from theliver is then drained through an isolation-aspiration catheter and thendirected outside the body to a filter system that reduces theconcentration of chemotherapeutic agent in the blood before this bloodis returned to the body.

Delivering high doses of chemotherapy (anti-cancer agents) to targetedorgans, detoxifying the blood using an extracorporeal circuit, andreturning the blood to a patient has been described in U.S. Pat. No.5,069,662 to Bodden.

SUMMARY

The present invention stems from the inventors realization that thereremains an urgent need to reduce the systemic levels of chemotherapeuticagents in cancer treatments and maintain the quality of the blood oftreated patients after external filtration. Advances in this area wouldsignificantly improve the prospects and quality of life for cancerpatients. The inventors recognized that to achieve the goals ofreducing, or eliminating, systemic effects of chemotherapy whiletargeting chemotherapy to specific organs, advances in our capacity toeffectively remove toxic small molecule chemotherapeutic agents fromblood were required. The present invention, in some embodiments,satisfies this urgent need by providing apparatus, systems, methods, andkits for high efficiency extracorporeal removal of small moleculechemotherapy agents from blood and blood products such as plasma whilemaintaining platelets, white blood cells and red blood cells in goodcondition. The greater efficiency of removal of chemotherapeuticsreduces systemic chemotherapeutic exposure and its associated toxicitiessuch as myelosuppression. Various embodiments of the invention areprovided below.

In some embodiments, provided herein is a filter apparatus for removingsmall molecule chemotherapy agents from blood comprising a housinghaving an inlet and an outlet, an extraction media comprising polymercoated carbon cores contained within the housing, wherein the carboncores have a pore volume of about 1.68 cc/g to about 2.17 cc/g.

In some embodiments provided herein is a filter apparatus for removingsmall molecule chemotherapy agents from blood comprising a housinghaving an inlet and an outlet, an extraction media comprising polymercoated carbon cores contained within the housing, wherein the carboncores have a pore volume of about 1.68 cc/g to about 2.17 cc/g and thecarbon cores have a particle diameter of about 0.45 mm to about 1.15 mm.

In some embodiments provided herein is a filter apparatus for removingsmall molecule chemotherapy agents from blood comprising a housinghaving an inlet and an outlet, an extraction media comprising polymercoated carbon cores contained within the housing, wherein the carboncores have a pore volume of about 1.68 cc/g to about 2.17 cc/g and theapparent density of carbon cores is about 0.19 to about 0.2.

In some embodiments provided herein is a filter apparatus for removingsmall molecule chemotherapy agents from blood comprising a housinghaving an inlet and an outlet, an extraction media comprising polymercoated carbon cores contained within the housing, wherein the carboncores have a pore volume of about 1.68 cc/g to about 2.17 cc/g and thecarbon cores have a median microporous diameter (D_(50,micro)) ofbetween about 9.3 Å to about 10.5 Å.

In some embodiments provided herein is a filter apparatus for removingsmall molecule chemotherapy agents from blood comprising a housinghaving an inlet and an outlet, an extraction media comprising polymercoated carbon cores contained within the housing, wherein the carboncores have a pore volume of about 1.68 cc/g to about 2.17 cc/g and amedian mesoporous diameter (D_(50,meso)) of between about 30 Å to about156 Å.

In some embodiments provided herein is a filter apparatus for removingsmall molecule chemotherapy agents from blood comprising a housinghaving an inlet and an outlet, an extraction media comprising polymercoated carbon cores contained within the housing, wherein the carboncores have a pore volume of about 1.68 cc/g to about 2.17 cc/g and thecarbon cores have a percent of microporous pores that represents betweenabout 18% to about 28% of the pore volume.

In some embodiments provided herein is a filter apparatus for removingsmall molecule chemotherapy agents from blood comprising a housinghaving an inlet and an outlet, an extraction media comprising polymercoated carbon cores contained within the housing, wherein the carboncores have a pore volume of about 1.68 cc/g to about 2.17 cc/g and thethe carbon cores have an MBET surface area of between about 1825 m²/g toabout 2058 m²/g.

In some embodiments provided herein is a filter apparatus for removingsmall molecule chemotherapy agents from blood comprising a housinghaving an inlet and an outlet, an extraction media comprising polymercoated carbon cores contained within the housing, wherein the carboncores have a pore volume of about 1.68 cc/g to about 2.17 cc/g and thecarbon cores have a DFT surface area of between about 1483 m²/g to about1778 m²/g.

In some embodiments provided herein is a filter apparatus for removingsmall molecule chemotherapy agents from blood comprising a housinghaving an inlet and an outlet, an extraction media comprising polymercoated carbon cores contained within the housing, wherein the carboncores have a pore volume of about 1.68 cc/g to about 2.17 cc/g and thehousing is a filter cartridge.

In some embodiments provided herein is a filter apparatus for removingsmall molecule chemotherapy agents from blood comprising a housinghaving an inlet and an outlet, an extraction media comprising polymercoated carbon cores contained within the housing, wherein the carboncores have a pore volume of about 1.68 cc/g to about 2.17 cc/g and thehousing is a filter cartridge and the small molecule chemotherapy agentis melphalan hydrochloride and the filter apparatus has an extractionefficiency of greater than 98% for removing melphalan hydrochloride fromblood using a filter cartridge in an in vitro system where blood flowthrough the filter cartridge is at about 250 mL/min.

In some embodiments provided herein is a filter apparatus for removingsmall molecule chemotherapy agents from blood comprising a housinghaving an inlet and an outlet, an extraction media comprising polymercoated carbon cores contained within the housing, wherein the carboncores have a pore volume of about 1.68 cc/g to about 2.17 cc/g and thehousing is a filter cartridge and the small molecule chemotherapy agentis melphalan hydrochloride and the filter apparatus has an extractionefficiency of between about 95% and about 98% for removing melphalanhydrochloride from blood using a filter cartridge in an in vitro systemwhere blood flow through the filter cartridge is at about 500 mL/min.

In some embodiments provided herein is a filter apparatus for removingsmall molecule chemotherapy agents from blood comprising a housinghaving an inlet and an outlet, an extraction media comprising polymercoated carbon cores contained within the housing, wherein the carboncores have a pore volume of about 1.68 cc/g to about 2.17 cc/g and thehousing is a filter cartridge and the small molecule chemotherapy agentis melphalan hydrochloride and the filter apparatus has an extractionefficiency of greater than about 95% for removing melphalanhydrochloride from blood using a filter cartridge in an in vitro system.

In some embodiments provided herein is a filter apparatus for removingsmall molecule chemotherapy agents from blood comprising a housinghaving an inlet and an outlet, an extraction media comprising polymercoated carbon cores contained within the housing, wherein the carboncores have a pore volume of about 1.68 cc/g to about 2.17 cc/g and thehousing is a filter cartridge and the small molecule chemotherapy agentis doxorubicin and the filter apparatus has an extraction efficiency ofgreater than about 95% for removing doxorubicin from blood using afilter cartridge in an in vitro system where blood flow through thefilter cartridge is at about 250 mL/min.

In some embodiments provided herein is a filter apparatus for removingsmall molecule chemotherapy agents from blood comprising a housinghaving an inlet and an outlet, an extraction media comprising polymercoated carbon cores contained within the housing, wherein the carboncores have a pore volume of about 1.68 cc/g to about 2.17 cc/g and thehousing is a filter cartridge and the small molecule chemotherapy agentis topotecan and the filter apparatus has an extraction efficiency ofgreater than about 89% for removing topotecan from blood using a filtercartridge in an in vitro system where blood flow through the filtercartridge is at about 250 mL/min.

In some embodiments of the filter apparatus for removing small moleculechemotherapy agents from blood, the polymer coated carbon cores arecoated with a semipermeable polymer coating comprised of materialselected from the group consisting of cellulose, a methacrylate polymer,and combinations thereof.

In some embodiments of the filter apparatus for removing small moleculechemotherapy agents from blood, the semipermeable polymer coating is amethacrylate selected from the group consisting ofpolymethylmethacrylate (PMMA), polyethylmethacrylate (PEMA),polyhydroxyethyl-methacrylate (PHEMA) and combinations thereof.

In some embodiments of the filter apparatus for removing small moleculechemotherapy agents from blood, the semipermeable polymer coating ispolyhydroxyethyl-methacrylate (PHEMA).

In some embodiments of the filter apparatus for removing small moleculechemotherapy agents from blood, the weight:weight ratio of carbon tomethacrylate is between 52:1 to 25:1.

In some embodiments, provided is a filter apparatus for removing smallmolecule chemotherapy agents from blood comprising a housing having aninlet and an outlet, an extraction media comprising polymer coatedcarbon cores contained within the housing, wherein the carbon cores havea pore volume of about 1.68 cc/g to about 2.17 cc/g and an MBET surfacearea of between about 1825 m²/g to about 2059 m²/g.

In some embodiments provided is a filter apparatus for removing smallmolecule chemotherapy agents from blood, wherein the carbon cores have apore volume of about 1.68 cc/g to about 2.17 cc/g, an MBET surface areaof between about 1825 m²/g to about 2059 m²/g and a DFT surface area isbetween about 1483 m²/g and about 1778 m²/g.

In some embodiments provided is a filter apparatus for removing smallmolecule chemotherapy agents from blood, wherein the carbon cores have apore volume of about 1.68 cc/g to about 2.17 cc/g, an MBET surface areaof between about 1825 m²/g to about 2059 m²/g a DFT surface area ofbetween about 1483 m²/g and about 1778 m²/g, and an apparent density ofbetween about 0.185 to about 0.195.

In some embodiments provided is a filter apparatus for removing smallmolecule chemotherapy agents, the small molecule chemotherapy agent ismelphalan hydrochloride and the filter apparatus has an extractionefficiency of greater than 98% for removing melphalan hydrochloride fromblood using a filter cartridge in an in vitro system where blood flowthrough the filter cartridge is at about 250 mL/min.

In some embodiments, provided is a filter apparatus for removingmelphalan hydrochloride from blood comprising a housing having an inletand an outlet, an extraction media comprising polymer coated carboncores contained within the housing, wherein the carbon cores have anapparent density of less than 0.2 g/cc and an extraction efficiency ofgreater than 98% for removing melphalan hydrochloride from blood.

In some embodiments, provided is a filter apparatus for removingmelphalan hydrochloride from blood comprising a housing having an inletand an outlet, an extraction media comprising polymer coated carboncores contained within the housing, wherein the carbon cores have anapparent density of less than 0.2 g/cc and an extraction efficiency ofgreater than 98% for removing melphalan hydrochloride from blood and thecarbon cores have a pore volume of about 1.68 cc/g to about 2.19 cc/g.

In some embodiments, provided is a filter apparatus for removingmelphalan having a concentration less than 15,000 ng/mL from blood,comprising one or more filter cartridge comprising an extraction mediacomprising polymer coated carbon cores contained within the filtercartridge, wherein the carbon cores have a pore volume of about 1.68 toabout 2.19 cc/g and an apparent density of less than about 0.2 g/cc, andwherein the filter apparatus has an extraction efficiency for melphalanof greater than 98% when blood flows through the filter apparatus at arate of 500 ml/L or less.

In some embodiments provided is a filter apparatus for removingmelphalan having a concentration less than 15,000 ng/mL from blood,comprising one or more filter cartridge comprising an extraction mediacomprising polymer coated carbon cores contained within the filtercartridge, wherein the carbon cores have a pore volume of about 1.68 toabout 2.19 cc/g and an apparent density of less than about 0.2 g/cc, andwherein the filter apparatus has an extraction efficiency for melphalanof greater than 98% when blood flows through the filter apparatus at arate of 500 ml/L or less, wherein the filter apparatus comprises twofilter cartridges.

In some embodiments provided is a filter apparatus for removingmelphalan having a concentration less than 15,000 ng/mL from blood,comprising one or more filter cartridge comprising an extraction mediacomprising polymer coated carbon cores contained within the filtercartridge, wherein the carbon cores have a pore volume of about 1.68 toabout 2.19 cc/g and an apparent density of less than about 0.2 g/cc, andwherein the filter apparatus has an extraction efficiency for melphalanof greater than 98% when blood flows through the filter apparatus at arate of 500 ml/L or less wherein the two filter cartridges are parallelto each other and flow is split such that fluid passes through the twofilter cartridges in parallel.

In some embodiments, provided is a method of treating a subject withcancer of the liver, comprising: isolating blood flow out of the liver;administering a chemotherapeutic agent arterially to the isolated liver;collecting blood laden with chemotherapeutic agent from the isolatedliver; and filtering the blood laden with chemotherapeutic agent with afilter apparatus comprising a housing having an inlet and an outlet, anextraction media comprising polymer coated carbon cores contained withinthe housing, wherein the polymer coated carbon cores have an apparentdensity of less than 0.21 g/cc.

In some embodiments, provided is a method of treating a subject withcancer of the liver, comprising: isolating blood flow out of the liver;administering a chemotherapeutic agent arterially to the isolated liver;collecting blood laden with chemotherapeutic agent from the isolatedliver; and filtering the blood laden with chemotherapeutic agent with afilter apparatus comprising a housing having an inlet and an outlet, anextraction media comprising polymer coated carbon cores contained withinthe housing, wherein the polymer coated carbon cores have an apparentdensity of less than 0.21 g/cc and wherein the chemotherapeutic agent ismelphalan hydrochloride. In some embodiments an extraction efficiency ofgreater than 98% for removing melphalan hydrochloride from blood isachieved. In some embodiments an extraction efficiency of greater than98% for removing melphalan hydrochloride from blood is achieved whenblood flow through the filter apparatus at a rate of about 500 ml/L orless.

In some embodiments, the carbon cores have an apparent density of lessthan 0.21 g/cc.

In some embodiments, provided is a method of treating a subject withcancer of the liver, comprising: isolating blood flow out of the liver;administering a chemotherapeutic agent arterially to the isolated liver;collecting blood laden with chemotherapeutic agent from the isolatedliver; and filtering the blood laden with chemotherapeutic agent with afilter apparatus comprising a housing having an inlet and an outlet, anextraction media comprising polymer coated carbon cores contained withinthe housing, wherein the polymer coated carbon cores have an apparentdensity of less than 0.21 g/cc and wherein the chemotherapeutic agentdoxorubicin or topotecan.

In some embodiments, provided is a method of treating a subject withcancer of the liver, comprising: isolating blood flow out of the liver;administering a chemotherapeutic agent arterially to the isolated liver;collecting blood laden with chemotherapeutic agent from the isolatedliver; and filtering the blood laden with chemotherapeutic agent with afilter apparatus comprising a housing having an inlet and an outlet, anextraction media comprising polymer coated carbon cores contained withinthe housing, wherein the polymer coated carbon cores have an apparentdensity of less than 0.21 g/cc and wherein the chemotherapeutic agent,wherein the filter apparatus comprises one or more filter cartridge.

In some embodiments, provided is a method of treating a subject withcancer of the liver, comprising: isolating blood flow out of the liver;administering a chemotherapeutic agent arterially to the isolated liver;collecting blood laden with chemotherapeutic agent from the isolatedliver; and filtering the blood laden with chemotherapeutic agent with afilter apparatus comprising a housing having an inlet and an outlet, anextraction media comprising polymer coated carbon cores contained withinthe housing, wherein the carbon cores have an apparent density of lessthan 0.21 g/cc and wherein the chemotherapeutic agent, furthercomprising returning the blood to the patient after it has been filteredto reduce the amount of chemotherapeutic agent in the blood.

In some embodiments provided is a method of treating cancer of the liverin a patient in need of treatment, comprising introducing a firstcatheter into a femoral artery to provide access to a region of theproper hepatic artery; guiding the first catheter to within the regionof the proper hepatic artery to deliver melphalan hydrochloride;inserting an isolation-aspiration catheter having two balloons, orexpandable occlusion means, into the femoral vein and guiding theisolation-aspiration catheter into the inferior vena cava; the twoballoons, or expandable occlusion means, are then inflated, or expanded,to block normal venous outflow of blood from the liver to the heart andisolate the liver; a dose of melphalan of from about 2.0 mg/kg to about3.5 mg/kg of the subjects body weight is delivered to the liver via thefirst catheter over a period of from about 15 minutes to about 45minutes; the melphalan-laden blood is then collected as it exits theliver in the region between the two inflated balloons, or expandableocclusion means, of the isolation-aspiration catheter and passed at arate of between about 250 ml/min and about 1000 ml/min through a filterapparatus in accordance with some embodiments of the inventions toremove greater than 98% of melphalan hydrochloride from the blood, andreturning blood that has been passed through the filter apparatus(filtered) to the patient through a third catheter placed in theinternal jugular vein.

In some embodiments, the invention provides a system for delivering ahigh concentration of a small molecule chemotherapeutic agent to asubject in need of treatment while minimizing systemic exposure to thesmall molecule chemotherapeutic agent, the system comprising a catheterinserted percutaneously into the inferior vena cava of a patient in needof treatment, the catheter comprising a hemo-compatible tube having acranial end and a caudal end, the hemo-compatible tube defining a mainlumen for outflowing blood, two balloons, fixedly spaced apart about thehemo-compatible tube and bonded thereto for inflation thereabout, onebeing contiguous to the cranial end, and the balloons, when inflated,having a size sufficient to block the flow of blood in a vein or arteryinto which the first catheter is designed to be inserted; fenestrationsin the hemo-compatible tube between the balloons to the main lumen;second and third lumina within the hemo-compatible tube, the secondlumen connecting to one of the balloons and the third lumen connectingto the other of the balloons, or other expandable devices, for effectinginflation or deflation of the balloons, the cranial end of thehemo-compatible tube effectively blocking inflow of blood; a filterapparatus in accordance with some embodiments of the invention forremoving the small molecule chemotherapeutic agents from blood, whereinthe filter apparatus is capable of being connected via a connector tothe first catheter and a flow machine for pumping the blood from thesubject through the filter apparatus, and a sheath or return catheterfor returning blood removed from the patient back to the patient afterfiltration.

In some embodiments the subject of the system for delivering a highconcentration of a small molecule chemotherapeutic agents is a human.

In some embodiments of the invention the system for delivering a highconcentration of a small molecule chemotherapeutic agent to a subjectcan be provided in the form of a kit of parts capable of beingassembled.

In other embodiments of the invention a series of hemofiltrationcartridges are used to provide a continuous source of fresh extractionmedia. In some embodiments of the invention the series of filters arechanged during a treatment by mechanical or electronic means in aposition before or after the pump in a hemofiltration circuit. In someembodiments a microprocessor is used to control the change of filters.In some embodiments, filter efficiency, or extraction efficiency, ismonitored in real time and filter cartridges are switched in response toany decreases in extraction efficiency. In some embodiments of theinvention a series of filter apparatus are arranged on a turntable likeapparatus or other structure that moves filter cartridges.

In some embodiments, the invention provides a method for delivering asmall molecule chemotherapeutic agents to a selected organ, or sectionof an organ, of a mammalian subject while restricting systemic exposureof the mammalian subject to the small molecule chemotherapeutic agent,comprising:

a. placing one or more catheters within the venous vasculature whichdrains the organ, at least one of the catheters having two or moreexpandable members;

b. isolating the organ, or section of the organ, by occluding flow ofblood within the venous vasculature which drains the organ, or sectionof the organ, by inflating the expandable members;

c. delivering the chemotherapeutic agent to the isolated organ orisolated section of the organ;

d. allowing the chemotherapeutic agent to perfuse within the isolatedorgan for a period of time sufficient to provide a therapeutic effect;

e. removing blood from the isolated organ, the blood comprising thesmall molecule chemotherapeutic agent,

f. filtering the blood to remove the small molecule chemotherapeuticagent by passing the blood through a filter apparatus for removing smallmolecule chemotherapy agents from blood comprising a housing having aninlet and an outlet, an extraction media comprising polymer coatedcarbon cores contained within the housing, wherein the carbon cores havea density of between about 0.185 g/mL and about 0.195 g/mL and thefilter apparatus has an extraction efficiency for the small moleculechemotherapy agents of greater than about 95%.

An important advantage of the high efficiency removal ofchemotherapeutic agents provided by the filter apparatus, systems,methods, and kits of some embodiments of the invention is that theyprovide for reduced systemic exposure to toxic chemotherapeutic agents(cancer drugs) leading to less bone marrow suppression which in turnreduces the incidence and severity of neutropenia, thrombocytopenia andanemia resulting in patients being able to continue treatments andsuffer less debilitating effects. The reduction in the frequency andseverity of these conditions decreases patient discomfort, suffering andsusceptibility to infection. This provides physicians with theopportunity to reinitiate treatments more rapidly than has been possiblebefore. Reduced systemic exposure to chemotherapy agents will alsoreduce the frequency and severity of other known toxicities includingbut are not limited to nausea, vomiting, oral ulceration, hair loss,interstitial pneumonitis, infertility, rash and itching.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an extracorporeal circuit as used for in vitro testing ofthe efficiency of filter apparatus.

FIG. 2 shows a system for carrying out chemosaturation with percutaneoushepatic perfusion.

DETAILED DESCRIPTION OF THE INVENTION

The inventors have surprisingly found that a filter apparatus comprisinga polymer coated low density activated carbon cores and systems,methods, and kits that use this filter apparatus can reduce theconcentration of low molecular weight chemotherapeutic agents(chemotherapy drugs), in some embodiments, at an efficiency greater than98%. While in preferred embodiments the invention is useful for removingsmall molecule chemotherapeutic agents from blood, some embodiments ofthe invention can be used to remove other toxic small molecule organiccompounds from blood or other body fluids.

In some embodiments the invention is particularly useful in percutaneoustechniques wherein specific organs have been isolated. An importantembodiment of the invention, because of the urgent need for newapproaches to treat primary and metastatic liver cancer, is to use thefilter apparatus of the invention as part of a percutaneous hepaticperfusion system to deliver high dose chemotherapy to the liver whilegreatly reducing systemic exposure to the chemotherapy. The filterapparatus as described herein, in some embodiments of the invention, canbe part of systems for percutaneous organ isolation and cancer treatmentas described, for example, in U.S. Pat. Nos. 5,069,662 and 5,411,479,both to Bodden, which are herein incorporated by reference. In U.S. Pat.Nos. 5,069,662 and 5,411,479, as here, an important application is thatof percutaneous hepatic perfusion.

In accordance with some embodiments of the invention high concentrationsof small molecule chemotherapy (anti-cancer agents) can be perfusedthrough a body organ containing a tumor and then removed from the organwith effluent blood. The blood contaminated with small moleculechemotherapy can then be transported to an extracorporeal circuitcomprising the filter apparatus described herein and the small moleculechemotherapy is removed from the blood with greater than 98% efficiencyand the purified blood is then returned to the body thereby providingfor infusion of much greater than usual doses of small moleculechemotherapy to the tumors while preventing toxic levels of the smallmolecule chemotherapy from entering the systemic system of the patient.

As used herein, “a” and “an” can mean one or more as is commonlyunderstood in patent claim construction.

As used herein “small molecule chemotherapy agents” refer to organiccompounds in the molecular weight range of about 200 to 1500 that areuseful as chemotherapy agents. Chemotherapy agents are drugs that areused to treat cancer in all forms. The terms chemotherapeutic agents,anti-cancer agents, chemotherapy, are all used interchangeably herein.

In some embodiments, the filtration apparatus of the invention is usedto remove small molecule chemotherapy agents from the blood of patientsundergoing chemotherapy targeted to cancers present in specific organs,glands or regions that can be isolated. For example, cancerous organssuch as the liver, kidney, pancreas, and bladder, glands such as theadrenals, pancreas, prostate, thyroid and parathyroid, and the pelvicregion are encompassed within the scope of the invention. For example,in some embodiments, the invention comprises a system, including thefilter apparatus, for isolation and treatment of cancers of the liver.However, embodiments of the present invention find application withtreatment of cancer with small molecule chemotherapy agents in anydiscrete isolatable region of the body.

In some embodiments, hypoxic abdominal perfusion (HAP) is used toisolate all or part of the abdominal cavity and before deliveringchemotherapeutic agent(s) to treat this cancers present in this region.In some embodiments, intraperitoneal hyperthermic chemotherapy (IPHC) isused to isolate the peritoneal cavity before administeringchemotherapeutic agent(s) to these regions. melphalan, paclitaxel orcombinations thereof to treat primary colorectal cancer. In someembodiments of the inventions, blood from these isolated regions isfiltered after chemotherapy treatment using the apparatus disclosedherein in its various embodiments.

Small molecule chemotherapy agents (anti-cancer agents) that can beremoved from blood in some embodiments of the invention includemelphalan hydrochloride (also known by persons of skill in the art asmelphalan, Alkaran, L-phenylalanine mustard, phenylalanine mustard,L-PAM, or L-sarcolysin), doxorubicin (also known as Adriamycin).Although not an exclusive list, other small molecule chemotherapy agentsthat can be removed from blood with some embodiments of the inventioninclude doxorubicin (Adriamycin), fluorinated pyrimidines(5-fluorouracyl 5-FU or floxuridine FURD), cisplatin, oxaliplatin,topotecan. Mytomycin C, cyclophosphamide, methotrexate, vincristine,Bleomycin, FAMT, and any other small molecule anti-cancer agents. Blooddetoxification can, for example, be achieved by hemoperfusion through afilter cartridge incorporating the filter apparatus described herein andin accordance with some embodiments of the invention.

The coating that surrounds the carbon cores in some embodiments iscomprised of poly(2-hydroxyethyl methacrylate). The thickness of thecoating that covers the particles is determined largely by the massratio of carbon cores to poly(2-hydroxyethyl methacrylate) used in thecoating process. In preparing the polymer cores the poly(2-hydroxyethylmethacrylate) is dissolved in ethanol and the carbon cores were soakedin the solution until dry, leaving a poly(2-hydroxyethyl methacrylate)coating on the particles. Weight:Weight ratios of carbon:poly(2-hydroxyethyl methacrylate ranging from 52:1 to 25:1 were testedand the extraction efficiencies during in vitro testing were found to bestatistically equivalent. In some embodiments of the invention theweight:weight ratios of carbon cores to poly(2-hydroxyethyl methacrylateare between 52:1 and 25:1. In other embodiments of the invention, theweight to weight ration of carbon cores to poly(2-hydroxyethylmethacrylate is about 25:1 (a 4% poly(2-hydroxyethyl methacrylate).

In some embodiments of the invention the small molecule chemotherapyagents are selected from melphalan, doxorubicin (also known ashydroxydaunorubicin and sold under the brand names Adriamycin,Adriamycin PFS, Adriamycin RDF, or Rubex), Docetaxel, paclitaxel,fluorinated pyrimidines (5-fluorouracyl 5-FU or floxuridine FURD),cisplatin, oxaliplatin, topotecan. Mytomycin C, cyclophosphamide,methotrexate, vincristine, Bleomycin, FAMT, pharmaceutically acceptablesalts thereof, combinations thereof, and other such compounds known topersons of skill in the art.

In some embodiments, pharmaceutically acceptable salts of any of thechemotherapeutic agents disclosed herein are used. The term“pharmaceutically-acceptable salts” embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable acidaddition salts of melphalan, paclitaxel, and oxaliplatin can be preparedfrom an inorganic acid or from an organic acid. Inorganic acids include,for example, hydrochloric, hydrobromic, hydroiodic, nitric, carbonic,sulfuric and phosphoric acid. Appropriate organic acids may be selectedfrom aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, example of which areformic, acetic, adipic, butyric, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic,4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, ethanedisulfonic, benzenesulfonic,pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,cyclohexylaminosulfonic, camphoric, camphorsulfonic, digluconic,cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic,nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic,persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic,tartaric, thiocyanic, mesylic, undecanoic, stearic, algenic,β-hydroxybutyric, salicylic, galactaric and galacturonic acid.Pharmaceutically-acceptable base addition salts include metallic salts,such as salts made from aluminum, calcium, lithium, magnesium,potassium, sodium and zinc, or salts made from organic bases includingprimary, secondary and tertiary amines, substituted amines includingcyclic amines, such as caffeine, arginine, diethylamine, N-ethylpiperidine, aistidine, glucamine, isopropylamine, lysine, morpholine,N-ethyl morpholine, piperazine, piperidine, triethylamine,trimethylamine. All of these salts may be prepared by conventional meansfrom the corresponding compound of the invention by reacting, forexample, the appropriate acid or base with the compound

In some embodiments, the chemotherapeutic agent is melphalan. Melphalanis marketed under the trade name Alkeran by GlaxoSmithKline, is acytotoxic and alkylating agent used in cancer chemotherapy. It is aphenyalanine derivative of nitrogen mustard, and is also referred to asL-phenylalanine mustard (L-PAM), phenyalanine mustard, or L-sarcolysin.The IUPAC systematic name is 4-[bis)2-chloroethyl)amino]-L-phenylalanine.

In some embodiments doxorubicin hydrochloride, also known ashydroxydaunorubicin is used and sold and marketed under the tradenames,Adriamycin PFS, Adriamycin RDF, or Rubex.

The filter apparatus, methods, and systems described herein can also beused for detoxification of the blood of patients having a variety ofsmall molecule poisons such as those associated with variousnon-therapeutic drugs, therapeutic drugs, and kidney failure.

As used herein “blood” can be blood as it is ordinarily found within amammalian subject, such as a human, but the term, as used herein, canalso refer to other blood products such as plasma.

As used herein in reference to the filter apparatus “housing” refers toa hemo-compatible and biocompatible structure with an inlet and anoutlet that is used to contain the extraction media. In some embodimentsthe housing can be a cylindrical structure with an inlet and an outlet.

As used herein, “filter cartridge” refers to a cylindrical column havinga length of about 7.8 inches between screens at the ends of the columnthat are used to contain filter media and a diameter of about 2.4inches, having an inlet and an outlet, comprised of a hemocompatiblethermoplastic material, and containing about 101 to 111 grams of filtermedia (extraction media), the filter media having a bulk volume range ofabout 535 mL to about 544 mL.

Thermoplastic material, as used herein, refers to polysulfone,polycarbonate, polyacrylic, polyurethane, and the like, as understood bypersons skilled in the art. Generally, polymers that provide rigidstructures that are hemocompatible can be used in embodiments describedherein. In some embodiments, the thermoplastic material is transparent.In some embodiments the thermoplastic material is a polysulfone.

As used herein, “polymer coating” refers to a semi-porous polymer thatcoats the activated carbon particles used in the present invention andrenders them hemocompatible. Suitable polymers that can be used for thispurpose include cellulose and polymers of methacrylate. For example, insome embodiments of the invention polymethylmethacrylate (PMMA),polyethylmethacrylate (PEMA), polyhydroxyethyl-methacrylate (PHEMA) andcombinations thereof can be used. While not exhaustive, other polymersthat can be used in some embodiments of the invention includepoly(N-vinylpyrrolidinone), poly(hydroxyethyl acrylate), hydroxyethylcellulose, hydroxypropyl cellulose, salts of poly(acrylic acid), saltsof poly(methacrylic acid), poly(dimethylaminoethyl methacrylate),poly(dimethylaminoethyl acrylate), poly(diethylaminoethyl acrylate),poly(diethylaminoethyl methacrylate), poly(vinyl alcohol), and the like.

Monomer starting materials that can be used for formation of the polymercoating in some embodiments of the invention include, for example,acrylic or (meth)acrylic acid derivatives including dimethylaminoethyl(meth)acrylate, diethylaminoethyl (meth)acrylate, dimethylaminopropyl(meth)acrylate, 3-dimethylamino-2-hydroxypropyl (meth)acrylate),acrylamide or methacrylamide derivative. In addition acrylamide andmethacrylamide such as N-dimethylaminoethyl (meth)acrylamide,N-diethylaminoethyl (meth)acrylamide can be used. Vinyl derivatives ofsuch nitrogen containing compounds such as 2-vinylpyridine,4-vinylpyridine, 2-methyl-5-vinylpyridine, 4-vinylimidazole,N-vinyl-2-ethylimidazole, vinylpyrrolidinone, N-vinyl-2-methylimidazole,can also be used in some embodiments of the invention. Combinations ofmonomers are also of use in some embodiments of the invention to form avariety of copolymers that persons of skill in the art would understandwould impart properties in accordance with some embodiments of theinvention.

In some embodiments the polymer coated carbon cores have an apparentdensity of between about 0.19 g/cc and 0.21 g/cc.

As used herein “density” or “apparent density” refers to the mass of apopulation of carbon cores divided by the total volume they occupy. Theterms “density” and “apparent density” are used herein interchangeably.

As used herein “extraction efficiency” refers to the results of thefollowing calculation for a single pass through a filter in accordancewith the following calculation: Extraction Efficiency=(Pre FilterConcentration-Post Filter Concentration/Pre Filter Concentration)×100

EXAMPLES

Materials

The coating material used in the examples, Poly (2-HydroxyethylMethacrylate), was purchased from Sigma Aldrich in powder form and isalso referred to herein as poly(2-HEMA) or poly-HEMA; Melphalen(Alkeran®) (2-amino-3-[4-[bis(2-chloroethyl)amino]phenyl]-propanoicacid) was purchased from BioNiche for animal studies and Sigma Aldrichfor in vitro experiments; Other chemicals, unless noted otherwise, werepurchased from Sigma Aldrich.) Hydrochloric Acid, 37%, Methanol≥99.8%,Sigma Aldrich

Bovine Blood and sodium heparin were purchased from Lampire(Pipersville, Pa.). Heparain was added before each run (1000 units/L).

Example 1: Preparation of Polymer Coated Carbon Cores (Activated CarbonMedia or Filter Media)

This example describes how to prepare polymer coated activated carbonparticles as used in the extraction media. Activated carbon or carboncan be purchased from commercial sources, for example Siemens or Rohm &Haas, or prepared in accordance with methods known in the art, see forexample, U.S. Pat. Nos. 3,909,449; 4,273,675; and 5,236,688 which areherein incorporated by reference. There is an extensive literature onactivated carbon characterization and preparation. See forexample“Active Carbon” by Bansal, R. C., Donnet, J. G., and Stoeckli, H.F., Marcel Dekker, New York, 1988, which is herein incorporated byreference. Activated carbon beads as starting materials were purchasedbut could also be prepared by blending petroleum pitch or coal pitchwith a viscosity-adjusting agent, melt molding the blend into spheres,extracting the agent by a solvent from the spheres and infusibilizingthe extract in accordance with practices well known to persons of skillin the art.

A further pyrolysis (carbonization) process was then used to tailor theactivated carbon particles to provide the properties effective inproducing the extraction media of the present invention. In thepyrolysis step a smoldering of the starting material was at hightemperatures, usually above 500° C., and preferably above 800° C.

The additional pyrolysis was carried out under conditions understood bypersons skilled in the art to create conditions of carbon decompositionthat provide pores and optimal surface area. The carbon decompositionunder high temperatures and varying the atmosphere from batch to batchselectively burns off regions of carbon providing the surface area, poresize, and density appropriate for the application of the presentinvention. Using this selective degradation, or oxidation, of theactivated carbon starting product and then testing in the filterapparatus of the present invention for absorbance capacity of smallmolecule chemotherapeutic agents, activated carbon cores (hereinafter“carbon cores”) were prepared.

The activated carbon cores (carbon cores) were then coated with apolymer coating that confers hemocompatibility. In the coating process,about 9.0 grams of Poly-HEMA (Poly (2-Hydroxyethyl Methacrylate)) wasslowly added to about 1800 ml ethanol while stirring at a temperature ofbetween about 60° C. and 80° C. for at least about 2 hours until thepoly-HEMA was dissolved producing a uniformly clear solution ofpoly-HEMA. The about 1800 ml of clear poly-HEMA solution was then pouredinto around 1200 ml of dry activated carbon cores and the mixture wasshaken for at least 27 hours until the product was free of liquid. Theactivated carbon cores were then dried by heating in an oven at about90° C. for at least 24 hours.

Example 2: Characterization of Carbon Cores

The Carbon Cores were characterized using a Quantachrome®ASiQwin(Autosorb IQ instrument) (Quantachrome Instruments), a Camsizer®(Retsch® Technology) and by weight.

For the Quantachrome®ASiQwin™, samples were placed in a clean and drysample cell and degassed at 300° C. for about 5 hours under vacuum.Samples were analyzed using nitrogen gas at about 77 K. Nitrogen wasintroduced under vacuum beginning at a partial pressure of 1.0e−7, andincrementally increasing to about 0.995 giving an adsorption curve.Nitrogen gas was then removed slowly until a partial pressure of 0.10was achieved, resulting in a desorption curve. The surface area was thenanalyzed using the Multi-point BET (MBET) method and the Quenched SolidDensity Functional Theory (QSDFT) method for slit/cylindrical pores withnitrogen at 77K to provide MBET and DFT surface areas. These methods areknown in the art, see, for example, “Characterization of Porous Solidsand Powders: Surface Area, Pore Size and Density,” Lowell et al.(Springer, 2006). Autosorb iQ software was used to make the calculationsusing the adsorption and desorption curves. The Multi-point BET surfacearea was analyzed for partial pressures between 0.005-0.200.

Density Functional Theory (DFT) is known in the art and is amolecular-based statistical thermodynamic theory that relates theadsorption isotherm to the microscopic properties of the system. The DFTmethod provides information on pore volume and surface area as afunction of half pore width whereas the MBET method provides totalsurface area.

As used herein, “micropores” are pores with half-pore widths (ordiameter, D) less than 20 Angstroms (Å).

As used herein, “mesopores” are pores with half-pore widths greater than20 Å and less than 250 Å.

As used herein, “the median diameter (D₅₀)”, refers to the diameter atwhich 50% of the sample pore volume is below the stated pore size, and50% of the sample pore volume is above the stated pore size. As usedherein, “D_(50,micro)” refers to the median pore diameter in themicroporous range.

As used herein “D_(50,meso)” refers to the median pore diameter in themesoporous range.

As used herein the term “% Microporous Pores” refers to the percentageof the pore volume occupied by micropores.

The carbon core diameter and solid density were measured according tomanufacturer instructions using a CAMSIZER®-L Digital Image ProcessingParticle Size and Shape Analyzer. (Retsch® Technology) The results areshown in

Table 1 below.

TABLE 1 Carbon Core Measurements Parameter Determined By Average RangeApparent Density (g/cc) Weighing 0.188 0.185-0.195 MBET Surface area(m2/g) Quantachrome 1946 1825-2058 DFT Surface area (m2/g) Quantachrome1644 1483-1778 Pore Volume (cc/g) Quantachrome 2.03 1.68-2.19 Pore SizeRange (Å) Quantachrome Median Microporous 9.7  9.3-10.5 Diameter, D₅₀,micro (Å) Median Mesoporous 105  30-156 Diameter, D₅₀, meso (Å) PercentMicroporous Quantachrome 22.37 18-28 Pores (%) Particle Diameter (mm)Camsizer 0.73 0.45-1.15

Example 3: Extraction Efficiency

Filter Cartridges Used in Extraction Efficiency and Animal Studies

A filter cartridge (cylindrical column) with a length of about 7.8inches between the screens used to contain filter media and a diameterof about 2.4 inches made of a thermoplastic material were filed withabout 101 to 111 grams of filter media having a bulk volume range ofabout 535 mL to about 544 mL were used. In some examples a single filtercartridge is used. In some examples two filter cartridges are used atthe same time. Unless indicated to be two cartridges, the data arereferring to the use of a single filter cartridge.

Example 3A: In Vitro Extraction Efficiency

The purpose of this example is to demonstrate the filter apparatuscapacity to extract a low molecular weight chemotherapeutic agent fromblood. Extraction efficiency was determined for using the extracorporealcircuit shown in FIG. 1.

In FIG. 1, a schematic of in vitro experimental circuit is shown. InFIG. 1, the various elements of the experimental circuit are illustratedas would be understood by persons of skill in the art. An apparatus forremoving small molecule chemotherapy agents from blood is shown 1. InFIG. 1, 2 indicates the sample port for obtaining a post-filter bloodsample, 3 indicates the waste line used for removing saline from thecircuit, 4 indicates the infusion pump for delivering thechemotherapeutic agent, 5 is a bag sample port, 6 is a sample port forobtaining a pre-filter blood sample.

Experimental Preparation

Bags were filled with approximately 2.5 L of blood and warmed to aminimum of 37° C. The blood was heparinized (1000 U/L) and the bags weresuspended in an incubator set at approximately 50° C.

The filter was primed and completely debubbled using normal saline.

The Delcath extracorporeal tubing pack was prepared according to thefollowing schematic.

Chemotherapeutic Preparation:

Melphalan Hydrochloride (HCl) was dissolved in a methanol andhydrochloric acid solution. The solution was then diluted with 0.9%saline.

Doxorubicin HCl was dissolved in 0.9% saline.

Topotecan was dissolved in dimethyl sulfoxide (DMSO) and then dilutedwith 0.9% saline.

Experimental Procedure

Syringes were filed with the chemotherapeutic solution and then attachedto the extracorporeal tubing through a two, one-way stop-cock circuitmeeting a ⅛″ female luer adapted to a two-way stop-cock within theextracorporeal circuit. An initial blood sample was obtained for abaseline chemotherapeutic concentration value. Blood was then runthrough the circuit, and fluid was directed through a waste line untilall visible saline was removed from the system. The waste line wasclamped off and the clamp on the circuit was released, forming thecomplete circuit. Chemotherapeutic was then infused into the circuit viaa syringe pump over 30 minutes.

Pre- and post-filter samples as well as samples from the blood bag werecollected at defined intervals throughout the procedure.

All samples were immediately placed on ice for less than 20 minutes andcentrifuged at 6,000 RPM for 10 minutes in a 4° C. refrigeratedcentrifuge. Samples were returned to ice after centrifugation and thesupernatant was transferred into microcentrifuge tubes. Samples werelater analyzed by liquid chromatography tandem mass spectrometry forchemotherapeutic concentration.

Sample Evaluation

All plasma samples were analyzed for the concentration ofchemotherapeutic via liquid chromatography tandem mass spectrometry.

Extraction efficiency at each time point was calculated using thefollowing equation:Extraction Efficiency=(Pre Filter Concentration-Post FilterConcentration/Pre Filter Concentration)×100

The mean extraction efficiency at each time point was used to determinethe overall efficiency for the individual experiment. The efficiencyreported for an experimental group is the mean efficiency of theexperiments within that group.

The Table 2 depicts the experimental results from several in vitrostudies utilizing bovine blood and

Table 3 shows the experimental results from an in vitro study usinghuman blood with melphalan hydrochloride.

TABLE 2 Summary of in vitro experiments with bovine blood Variables FlowRate Hydrogel Ratio Sample per cartridge (g media/g Efficiency (%)Chemotherapeutic Dose (mg) Size (ml/min) hydrogel) Average RangeMelphalan HCl 110 6 250 25:1 99.1 98.5-99.7 Melphalan HCl 110 36 50025:1 97.2 95.0-98.5 Doxorubicin HCl 150 5 400 25:1 95.4 93.4-96.8Doxorubicin HCl 90 2 250 25:1 96.4 95.9-97.0 Doxorubicin HCl 150 2 40025:1 96.9 96.9-96.9 Topotecan 6.25 3 250 25:1 90.3 89.4-91.2 12.5 18.75Topotecan 6.25 3 500 25:1 84.3 84.0-85.0 12.5 18.75

TABLE 3 Summary of in vitro experiment with human blood and melphalanhydrochloride Variables Flow Rate Hydrogel Ratio Sample per cartridge (gmedia/g Efficiency (%) Chemotherapeutic Dose (mg) Size (ml/min)hydrogel) Average Range Melphalan HCl 110 4 250 25:1 99.4 99.2-99.5Melphalan HCl 110 3 500 25:1 96.7 96.3-97.2

Example 3B: In Vivo Extraction Efficiency

This example demonstrates the chemotherapeutic extraction efficienciesachieved in a porcine model of chemosaturation with percutaneous hepaticperfusion (CS-PHP) with two filter cartridges arranged in parallel.

Animals and Pre-Operative Care

Yorkshire Cross pigs (4-6 months, approximately 158-216 lbs) were usedin four acute studies. Food was withheld approximately 12-24 hoursbefore surgery.

General anesthesia was induced and a cuffed endotracheal tube wasinserted. An IV catheter was placed for fluid and drug administration.General anesthesia was maintained with Isoflurane delivered in oxygenthrough an anesthesia unit. A ventilator was used to assist respiration.

Surgical Procedure

An experimental porcine model of percutaneous hepatic perfusion wasused. A schematic representation of the CS-PHP system with experimentalsample ports and pressure monitoring sites included is shown in FIG. 2.FIG. 2 shows a system according to some embodiments of the presentinvention for chemosaturation with percutaneous hepatic perfusion isshown. The various elements are understood by persons of skill in theart. In FIG. 2, 9 shows two filter apparatus arranged in parallel forremoving small molecule chemotherapy agents from blood, 10 shows asample port for obtaining post-filter blood samples, 11 shows an atrialfilter, or bubble trap for reducing the risk of air bubbles entering thesystemic circulation, 12 shows a systemic venous return sheath placed inthe internal jugular vein, 13 shows a sampling port placed in thecarotid artery, 14 a double balloon catheter placed in the inferior venacava such as the one used in Delcath's Chemosat® system, shows a hepaticarterial Infusion Catheter for chemotherapeutic administration, 16 showsintroducer sheaths in the femoral vein and femoral artery, 17 shows asample port for obtaining pre-filter blood samples and 18 shows a filterbypass.

Using standard cut down techniques or percutaneous placement, anintroducer sheath was placed in the femoral vein (for insertion of thedouble balloon catheter), femoral artery (for insertion of the hepaticarterial delivery catheter and monitoring of invasive blood pressure),jugular vein (for blood return) and carotid artery (for systemic bloodsampling). Once the sheaths were placed, heparin (˜300 IU/kg) wasadministered. Coagulation was assessed by activated clotting time (ACT),with a target ACT≥300 seconds. ACT was monitored throughout theprocedure and additional heparin was administered as needed.

Using fluoroscopic guidance, the hepatic arterial catheter was placedbeyond the gastroduodenal artery in preparation to deliver thechemotherapeutic agent. Under fluoroscopic guidance, the double ballooncatheter was advanced over a guide wire into the inferior vena cava, andthe tip positioned at the level of the diaphragmatic hiatus. The venouscatheter was connected to the hemofiltration circuit and the venousreturn sheath was connected to the perfusion adapter. The entire systemwas purged of air.

Once the hemofiltration circuit was established, venous blood wasaspirated from the central lumen through the fenestration in the doubleballoon catheter. The blood flowed through the double balloon catheterto the pump, through the filter, and returned to the animal via thevenous return sheath.

The two balloons in the double balloon catheter were inflated withdilute contrast media prior to drug infusion. The cephalad balloonoccluded the inferior vena cava above the highest hepatic vein and thecaudal balloon occluded the inferior vena cava below the lowest hepaticvein. The hemofiltration system was brought online. Once thehemofiltration circuit was running satisfactorily administration of thechemotherapeutic agent began.

In some studies, phenylephrine was administered throughout the course ofthe procedure, as needed, to maintain mean arterial pressure. Boluses ofsodium bicarbonate may have been administered to maintain pH at anacceptable level. Dextrose saline (5%) may have been administeredintravenously in addition to normal saline throughout the procedure.

The chemotherapeutic agent was administered through the hepatic arterialcatheter over a 30-minute “infusion period” Following the infusion ofdrug, a 30-minute “washout period” was performed where extracorporealfiltration was continued.

At the end of the procedure, blood flow to the filter cartridges wasstopped one at a time by closing the appropriate attached clamps on thecircuit tubing. The IsoFuse caudal balloon was then deflated followed bythe deflation of the cephalad balloon. All catheters were removed fromthe animal and the animal was euthanized while under general anesthesia.

Sample Collection

Plasma samples were generated from blood collected at ports within theextracorporeal circuit before and after the arterial filter to determinethe chemotherapeutic removal efficiency of the filter. Plasma samplesgenerated from systemic blood were used to determine the total systemicdose that the animals received.

An initial systemic plasma sample was generated from blood drawn fromthe internal carotid artery immediately before the initiation ofchemotherapeutic infusion to obtain a baseline systemic PK.

During the infusion and post infusion periods, pre-filter, post-filter,and systemic plasma samples were generated from blood drawn at definedintervals, starting at the beginning of infusion until the end of thewashout period.

Once each blood sample was drawn they were immediately placed on wetice. Samples were centrifuged at approximately 3600 RCF forapproximately 10 minutes at approximately 4° C. and placed on wet iceuntil further processing. Plasma from each sample was aliquoted into amicrocentrifuge tube. Plasma samples were stored at −80° C. within twohours of the initial blood draw.

Sample Evaluation

Plasma samples were analyzed for the concentration of chemotherapeuticvia liquid chromatography tandem mass spectrometry.

Extraction efficiency at each time point was calculated using thefollowing equation:Extraction Efficiency=(Pre Filter Concentration-Post FilterConcentration/Pre Filter Concentration)×100

The mean extraction efficiency at each time point was used to determinethe overall efficiency for the individual animals. The efficiencyreported for a study is mean efficiency of the animals within thatstudy.

Table 4 is a summary of parameters in each porcine animal study andresulting extraction efficiencies from the 60 minutes of hemofiltration.

TABLE 4 Summary of Animal Studies Study 1 2 3 4 Sample Size  6  5 10  5Chemotherapeutic Melphalan Melphalan Melphalan Doxorubicin HCl HCl HClHCl Dose (mg) 220  209  220  152  Procedure Length (min) Infusion Period30 30 30 30 Washout Period 30 30 30 30 Overall 60 60 60 60 Phenylephrine(Yes No Yes Yes Yes or No) Bicarbonate (Yes No Yes Yes Yes or No)Dextrose (5%) Saline No No No Yes (Yes or No) Animal Weight Range206-216 158-209 169-209 158-180 (lbs) Target Flow Rate 500  500  500 500  (mL/min) Hydrogel Ratio (g 25 25 25 25 media/g hydrogel) SamplingInterval  3  6  6  5 (min) Chemotherapeutic Removal Efficiency (%)Average ± 98.5 ± 0.5 96.3 ± 0.3 97.5 ± 0.5 71.4 ± 5.1 Standard DeviationRange 97.8-99.1 96.0-96.7 96.4-98.2 65.4-79.2

What is claimed is:
 1. A kit of parts capable of being assembled fordelivering a small molecule chemotherapeutic agent to a subject,comprising: a double balloon catheter; a filter apparatus comprising ahousing having an inlet and an outlet, an extraction media comprisinghemocompatible polymer coated carbon cores contained within the housing,wherein the carbon cores have a pore volume of about 1.68 cc/g to about2.17 cc/g.
 2. A kit of parts capable of being assembled for delivering asmall molecule chemotherapeutic agent to a subject according to claim 1,wherein the carbon cores have a particle diameter of about 0.45 mm toabout 1.15 mm.
 3. A kit of parts capable of being assembled fordelivering a small molecule chemotherapeutic agent to a subjectaccording to claim 1, wherein the apparent density of carbon cores isabout 0.19 g/cc to about 0.2 g/cc.
 4. A kit of parts capable of beingassembled for delivering a small molecule chemotherapeutic agent to asubject according to claim 1, wherein the carbon cores have a medianmicroporous diameter (D_(50, micro)) of between about 9.3 Å to about10.5 Å.
 5. A kit of parts capable of being assembled for delivering asmall molecule chemotherapeutic agent to a subject according to claim 1,wherein the carbon cores have a median mesoporous diameter (D_(50,meso))of between about 30 Å to about 156 Å.
 6. A kit of parts capable of beingassembled for delivering a small molecule chemotherapeutic agent to asubject according to claim 1, further comprising a catheter forproviding access to a hepatic artery and/or a sheath or return catheterfor returning blood to a patient after the blood has been filtered toreduce the amount of chemotherapeutic agent in the blood.
 7. A kit ofparts capable of being assembled for delivering a small moleculechemotherapeutic agent to a subject according to claim 1, wherein thesmall molecule chemotherapeutic agent is melphalan hydrochloride.
 8. Akit of parts capable of being assembled for delivering a small moleculechemotherapeutic agent to a subject according to claim 1, wherein thefilter apparatus comprises one or more filter cartridges.
 9. A kit ofparts capable of being assembled for delivering a small moleculechemotherapeutic agent to a subject according to claim 1, wherein thefilter apparatus comprises a dual filter cartridge wherein the dualfilter cartridge comprises filter cartridges arranged in parallel.
 10. Akit of parts capable of being assembled for delivering a small moleculechemotherapeutic agent to a subject according to claim 1, wherein thehemocompatible polymer coated carbon cores contained within the housingare coated with a semipermeable polymer coating comprised of materialselected from the group consisting of cellulose, a methacrylate polymer,and combinations thereof.
 11. A kit of parts capable of being assembledfor delivering a small molecule chemotherapeutic agent to a subjectaccording to claim 10, wherein the semipermeable polymer coating is amethacrylate selected from the group consisting ofpolymethylmethacrylate (PMMA), polyethylmethacrylate (PEMA),polyhydroxyethyl-methacrylate (PHEMA) and combinations thereof.
 12. Akit of parts capable of being assembled for delivering a small moleculechemotherapeutic agent to a subject according to claim 11, wherein thesemipermeable polymer coating is polyhydroxyethyl-methacrylate (PHEMA).13. A kit of parts capable of being assembled for delivering a smallmolecule chemotherapeutic agent to a subject according to claim 1,wherein the subject is a human.
 14. A kit of parts capable of beingassembled for delivering a small molecule chemotherapeutic agent to asubject according to claim 1, further comprising the small moleculechemotherapeutic agent melphalan hydrochloride.
 15. A kit of partscapable of being assembled for delivering a small moleculechemotherapeutic agent to a liver of a patient, comprising: anisolation-aspiration catheter which comprises two balloons, and a filterapparatus comprising a housing having an inlet and an outlet, anextraction media comprising hemocompatible polymer coated carbon corescontained within the housing, wherein the polymer coated carbon coreswherein the carbon cores have a pore volume of about 1.68 cc/g to about2.17 cc/g.
 16. A kit of parts capable of being assembled for deliveringa small molecule chemotherapeutic agent to a liver of a patientaccording to claim 15, further comprising a chemotherapeutic agentselected from melphalan, doxorubicin, 5-fluorouracyl 5-FU, floxuridineFURD, cisplatin, oxaliplatin, topotecan, mytomycin C, cyclophosphamide,methotrexate, vincristine, Bleomycin, FAMT, or combinations thereof. 17.A kit of parts capable of being assembled for delivering a smallmolecule chemotherapeutic agent to a liver of a patient according toclaim 15, further comprising melphalan hydrochloride.
 18. A kit of partscapable of being assembled for delivering a small moleculechemotherapeutic agent to a liver of a patient according to claim 15,further comprising an extracorporeal circuit.
 19. A kit of parts capableof being assembled for delivering a small molecule chemotherapeuticagent to a liver of a patient according to claim 15, further comprisingan infusion catheter.
 20. A system comprising a circuit of catheters fordelivering a high concentration of a small molecule chemotherapeuticagent to a subject in need of treatment while minimizing systemicexposure to the small molecule chemotherapeutic agent, comprising: acatheter inserted percutaneously into the inferior vena cava of apatient in need of treatment, the catheter comprising a hemo-compatibletube having a cranial end and a caudal end, the hemo-compatible tubedefining a main lumen for outflowing blood, two balloons, fixedly spacedapart about the hemo-compatible tube and bonded thereto for inflationthereabout, one being contiguous to the cranial end, and the balloons,when inflated, having a size sufficient to block the flow of blood in avein or artery into which the first catheter is designed to be inserted;fenestrations in the hemo-compatible tube between the balloons to themain lumen; second and third lumina within the hemo-compatible tube, thesecond lumen connecting to one of the balloons and the third lumenconnecting to the other of the balloons, or other expandable devices,for effecting inflation or deflation of the balloons, the cranial end ofthe hemo-compatible tube effectively blocking inflow of blood, and afilter apparatus comprising a housing having an inlet and an outlet, anextraction media comprising hemocompatible polymer coated carbon corescontained within the housing, wherein the polymer coated carbon coreshave a pore volume of about 1.68 cc/g to about 2.17 cc/g, wherein thefilter apparatus is capable of being connected via a connector to thefirst catheter and a flow machine for pumping the blood from the subjectthrough the filter apparatus, and a sheath or return catheter forreturning blood removed from the patient back to the patient afterfiltration.
 21. A system according to claim 20, wherein the carbon coreshave a particle diameter of about 0.45 mm to about 1.15 mm.
 22. A systemaccording to claim 20, wherein the apparent density of carbon cores isabout 0.19 g/cc to about 0.2 g/cc.
 23. A system according to claim 20,wherein the carbon cores have a median microporous diameter (D50, micro)of between about 9.3 Å to about 10.5 Å.
 24. A system according to claim20, wherein the carbon cores have a median mesoporous diameter(D50,meso) of between about 30 Å to about 156 Å.
 25. A kit of partscapable of being assembled for delivering a small moleculechemotherapeutic agent to a liver of a patient according to claim 15,wherein the carbon cores have a particle diameter of about 0.45 mm toabout 1.15 mm.
 26. A kit of parts capable of being assembled fordelivering a small molecule chemotherapeutic agent to a subjectaccording to claim 15, wherein the apparent density of carbon cores isabout 0.19 g/cc to about 0.2 g/cc.
 27. A kit of parts capable of beingassembled for delivering a small molecule chemotherapeutic agent to asubject according to claim 15, wherein the carbon cores have a medianmicroporous diameter (D50, micro) of between about 9.3 Å to about 10.5Å.
 28. A kit of parts capable of being assembled for delivering a smallmolecule chemotherapeutic agent to a subject according to claim 15,wherein the carbon cores have a median mesoporous diameter (D50,meso) ofbetween about 30 Å to about 156 Å.